The present invention relates to a mammalian Cxe2x80x94C chemokine production inhibitor comprising a prostanoic acid derivative as an active component.
In 1987, Matsushima et al. isolated IL-8 as a neutrophilic chemotactic factor from a culture supernatant of human peripheral blood monocytes stimulated by a popolysaccharide LPS, and then purified and cloned molecules having a migrating activity for many leukocytes. These molecules have a common structure, and are thus generically named xe2x80x9cchemokinexe2x80x9d. Chemokine mainly has high affinity for heparin, and the common property that it is synthesized as a precursor composed of about 100 amino acids, and then secreted in a mature type comprising about 70 amino acids.
Chemokine generally has four cysteine residues, and is roughly classified into Cxe2x80x94Xxe2x80x94C chemokine comprising an amino acid held between the first two cysteine residues, and Cxe2x80x94C chemokine having no amino acid between the cysteine residues. Cxe2x80x94Xxe2x80x94C chemokine is also called xcex1 chemokine, and Cxe2x80x94C chemokine is called xcex2 chemokine. The Cxe2x80x94C chemokine family is a generic name of a group of low-molecular-weight proteins having about 30% of homology at the amino acid level, and cysteine at the same four positions.
Monocyte chemoattractant protein-1 (MCP-1) also named a monocyte chemotactive activating factor (MCCAF) or glioma-derived monocyte chemotactic factor(GDCF), and is a Cxe2x80x94C chemokine protein comprising 76 amino acids and four cysteine residues. The identification and gene cloning of MCAF, MCP-1 or GDCF have been reported (K. Matsushima et al., J. Exp. Med., 169, 1485-1490, 1989, Y. Furutani et al., Biochem. Biophys. Res. Commun., 159, 249-255, 1989, E. R. Robinson et al., Proc. Natl. Acad. Sci. USA, 86, 1850-1854, 1989, T. Yoshimura et al., FEBS Letters, 244, 487-493, 1989) These documents also disclose methods of producing MCP-1. In the present invention, MCP-1 is an abbreviated name and includes GDCF and MCAF hereinafter.
MCP-1 is produced from hemocytic cells such as monocytes, macrophages, and lymphocytes, as well as various cells such as fibroblasts, endothelial cells, smooth muscle cells, various tumor cells, and the like by stimulation with IL-1, TNF, IFNxcex3-, LPS, phorbol ester (TPA), or the like, and MCP-1 is known to cause accumulation of very strong monocytes and/or macrophages in a pathogenic region. MCP-1 also has a chemotactic action and activating action on basophils and T cells.
Other known proteins belonging to the Cxe2x80x94C chemokine family include RANTES, LD78, ACT2, I-309, MCP-2, MCP-3, JE, MIP-1xcex1, MIP-1xcex2, TCA-3, eotaxin, and the like. Of these proteins, MCP-2, MCP-3 (K. B. M. Reid, Immunol. Today 10, 177-180, 1989), RANTES (P. N. Barlow et al., J. Mol. Biol. 232, 268-284, 1993), and JE (B. J. Rollins et al., Proc. Natl. Acad. Sci. USA, 85, 3738-3742, 1988) are known to induce chemotaxis of monocytes and/or macrophages to a pathogenic region. RANTES also exhibits the strong chemotactic ability for basophils, eosinophils, and T-cells, and is related to chronic rheumatoid arthritis, endarterial hyperplasia after organ transplantation, rejection after organ transplantation, and allergic diseases. MIP-1xcex1 is known to exhibit the chemotactic action on basophils, eosinophils, T-cells, B-cells, and NK-cells, and eotaxin has strong chemotactic action on eosinophils.
Pathological progress of migration of eosinophils and basophils is frequently observed in acute serious inflammation, chronic intractable inflammation, bronchial asthma, allergic diseases, parasitic diseases, tumors, eosinophilic gastroenteritis, peptic ulcer, valvular diseases, multiple sclerosis, osteoporosis, and organ re-perfusion disorder. Although migration of monocytes and macrophages to a pathogenic region is also observed in general inflammation, it is observed particularly in acute serious inflammation, chronic intractable inflammation, and allergic diseases, and also observed in nephritis, pneumonocirrhosis, arteriosclerosis, and malignant tumors.
It is known that diabetes highly frequently causes great vessel diseases such as arteriosclerosis, and microangiopathy causing complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, and the like. However, it is thought to be important for the angiopathy that microphages are bonded to the endothelial cells and infiltrated into the vessel walls.
It is also known that in lung diseases, microphages are increased in the lung, and macrophages play an important role for fibrogenesis in the lung. Accumulation of macrophages is also observed in an affected part of chronic rheumatoid arthritis (RA).
Conventionally, a steroidal agent or non-steroidal anti-inflammatory agent is used for the above-described diseases. However, such medicines are known to suppress leukocyte migration, and at the same time, suppress the functions of many types of cells, thereby causing the problem of causing various serious side effects.
Prostaglandin (PG) includes a group of compounds naturally existing, exhibiting a variety of physiological activities, and having a common prostanoic acid skeleton. The natural PG compounds are classified into PGA, PGB, PGC, PGD, PGE, PGF, PGG, PGH, PGI, and PGJ by the structural characteristics of five-member rings, and further classified into sub-classes 1, 2, 3, etc. by the presence of unsaturation and oxidation. Also, many synthetic compounds analogous to these PG compounds are known. Of these PG compounds, a typical PGI derivative PGI2 is referred to as xe2x80x9cprostacyclinxe2x80x9d (refer to Nature, Vol. 268, p688, 1976), and is known as a substance having strong platelet aggregation inhibiting action and peripheral vasodilating action. As compounds in which instability of the PGI2 is significantly improved, Japanese Examined Patent publication Nos. 2-12226, 2-57548 and 1-53672 disclose PGI2 derivatives having a skeleton in which the structure of an exoenol ether portion, which is a characteristic structure of PGI2, is converted into an inter-m-phenylene type. Other known compounds in which stability of prostaglandin is improved include ataprost, iloprost, clinprost, ciprosteni, naxaprost, taprostene, cicaprost, pimilprost, CH-169, and CS570 (refer to Gendai-Iryosha, xe2x80x9cGenerals of Prostaglandinxe2x80x9d No. 1, p. 123, 1994; New Drugs of Tomorrow, p. 15-IV-185, 1996; New Drugs of Tomorrow, p. 15-III-551, 1996). However, it is unknown that these prostanoic acid derivatives have the action to inhibit directly Cxe2x80x94C chemokine production.
It is an object of the present invention to provide a preventive and curative medicine for diseases for which conventional medicines are ineffective and cause serious side effects, such diseases being characterized by abnormal accumulation or activation of leukocytes such as monocytes and/or macrophages, eosinophils, basophils, and the like.
The present invention provides a Cxe2x80x94C chemokine production inhibitor comprising a prostanoic acid derivative as an active component.